Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Suppression of the gastrin gene in human colon cancer cells by stably expressing antisense (AS) gastrin RNA results in significant growth suppression of AS cells. To understand mechanisms mediating the growth effects of autocrine gastrins, differential expression of transcripts by AS and control (C) clones of a representative cell line (HCT-116) was analyzed to identify target genes of autocrine gastrins. Six differentially expressed transcripts were confirmed and sequenced. Of these, the RNA and protein levels of cytochrome c oxidase (COX) Vb were significantly higher in C versus AS cells. The expression of COX Vb by colon cancer cells was proportional to the expression of gastrin. Higher levels of COX Vb coprecipitated with cytochrome c in the mitochondria of C versus AS cells. Treatment of mitochondria with digitonin resulted in a 2-fold higher release of cytochrome c from AS versus C mitochondria. As a corollary, the cytosolic levels of cytochrome c were significantly higher in AS versus C cells, which correlated with approximately 2- and approximately 3-fold higher activation of caspase-9 and -3, respectively, in AS versus C cells in response to camptothecin. Thus, autocrine gastrins may support growth/survival of cells by up-regulating COX Vb, which may decrease the sensitivity of the cancer cells to apoptotic stimuli by increasing retention of cytochrome c in mitochondria.
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PMID:Autocrine gastrins in colon cancer cells Up-regulate cytochrome c oxidase Vb and down-regulate efflux of cytochrome c and activation of caspase-3. 1091 81

Mutations in the adenomatous polyposis coli (APC) tumor suppressor gene occur in most colorectal cancers and lead to activation of beta-catenin. Whereas several downstream targets of beta-catenin have been identified (c-myc, cyclin D1, PPARdelta), the precise functional significance of many of these targets has not been examined directly using genetic approaches. Previous studies have shown that the gene encoding the hormone gastrin is activated during colon cancer progression and the less-processed forms of gastrin are important colonic trophic factors. We show here that the gastrin gene is a downstream target of the beta-catenin/TCF-4 signaling pathway and that cotransfection of a constitutively active beta-catenin expression construct causes a threefold increase in gastrin promoter activity. APC(min-/+) mice overexpressing one of the alternatively processed forms of gastrin, glycine-extended gastrin, show a significant increase in polyp number. Gastrin-deficient APC(min-/+) mice, conversely, showed a marked decrease in polyp number and a significantly decreased polyp proliferation rate. Activation of gastrin by beta-catenin may therefore represent an early event in colorectal tumorigenesis and may contribute significantly toward neoplastic progression. The identification of gastrin as a functionally relevant downstream target of the beta-catenin signaling pathway provides a new target for therapeutic modalities in the treatment of colorectal cancer.
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PMID:Gastrin is a target of the beta-catenin/TCF-4 growth-signaling pathway in a model of intestinal polyposis. 1095 28

Serum gastrin is known to be elevated in patients with liver-metastasizing colon cancer; thus, cholecystokinin (CCK) B/gastrin receptors may also be up-regulated. A liver-invasive model of colon cancer was established with the human colonic cell line C170HM2, which expresses the CCKB/gastrin receptor at both the gene and protein level. An antiserum has been derived that is directed against the NH2-terminal 17 amino acids of the human CCKB/gastrin receptor coupled to diphtheria toxoid. The peptide was denoted gastrin receptor protein (GRP) 1. The therapeutic effect of GRP1 antiserum was evaluated on the liver invasion of C170HM2 tumors. Biodistribution studies revealed that GRP1 antiserum localized preferentially within the liver tumors when compared with normal liver tissue (1.5-fold increase after 24 h; P < 0.05). Antiserum against GRP1 inhibited both tumor take rate and final liver tumor weight when compared with treatment with control serum in mice with an increasing tumor burden. Liver tumor weights were reduced from 0.37 to 0.10 gram (P = 0.0155), 1.25 grams to 0.76 gram (P = 0.003) and 1.89 grams to 0.76 gram (P = 0.0068, all Mann-Whitney nonparametric U test). Necrosis and apoptosis were increased in the GRP1 antiserum-treated tumors when compared with control serum-treated tumors. As shown by Western blotting, CCKB/gastrin receptor expression of C170HM2 xenografts after treatment with GRP1 antiserum shifted to a predominantly lower molecular weight form (Mr 45,000) that is known to be an internalized form of the receptor. In conclusion, targeting of the CCKB/gastrin receptor may yield a valuable therapeutic modality for the treatment of advanced colon cancer.
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PMID:Antiserum raised against an epitope of the cholecystokinin B/gastrin receptor inhibits hepatic invasion of a human colon tumor. 1105 89

Regardless of the type and dose of beverage involved, alcohol facilitates the development of gastroesophageal reflux disease by reducing the pressure of the lower esophageal sphincter and esophageal motility. Fermented and nondistilled alcoholic beverages increase gastrin levels and acid secretion. Succinic and maleic acid contained in certain alcoholic drinks also stimulate acid secretion. Low alcohol doses accelerate gastric emptying, whereas high doses delay emptying and slow bowel motility. Alcohol facilitates the development of superficial gastritis and chronic atrophic gastritis--though it has not been shown to cause peptic ulcer. Alcoholic beverages, fundamentally wine, have important bactericidal effects upon Helicobacter pylori and enteropathogenic bacteria. The main alcohol-related intestinal alterations are diarrhea and malabsorption, with recovery after restoring a normal diet. Alcohol facilitates the development of oropharyngeal, esophageal, gastric, and colon cancer. Initial research suggests that wine may be comparatively less carcinogenic.
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PMID:The effects of alcohol consumption upon the gastrointestinal tract. 1115 64

It is well known that 5-fluorouracil (5-FU) is the most effective drug in the treatment of colon cancer, however the positive response is small, only about 20%. On the other hand, it has been postulated that the growth of colon cancer depends on many growth factors, such as gastrin and estrogens. The search for new substances increasing the antitumor effect of 5-FU has lasted for many years. The aim of the present study was to examine the effects of pentagastrin (PEN, syntetic gastrin analogue), proglumide (PRO, a blocker of gastrin receptor) and tamoxifen (TAM, a partial estrogen antagonist) given separately or together with 5-FU on proliferation, apoptosis, necrosis and proliferation/apoptosis (P/A) ratio in the murine transplantable Colon 38 cancer. The male mice were implanted with a suspension of Colon 38 cells. After 7 days, the animals were treated with PEN (250 microg/kg b.w., twice daily), PRO (100 mg/kg. b.w., twice daily), TAM (10 microg/animal) separately or together with 5-FU (60 mg/kg b.w., once) for 2 days. The incorporation of bromodeoxyuridine (BrdU) into cell nuclei was used as an index of cell proliferation (labeling index--LI). The in situ labeling of nuclear DNA fragmentation according to TUNEL method was considered as an apoptotic index (AI). It was found that 5-FU increased the apoptosis, unexpectedly increased the LI and decreased the P/A ratio when compared to control. Both PEN and PRO increased the apoptosis and in the case of PRO decreased P/A ratio when compared to control. TAM did not affect any of the examined parameters. All of the investigated substances modify the 5-FU action: PEN and PRO on AI and LI and TAM on AI and P/A ratio. Necrosis was observed in 3 tumors treated with PEN + 5-FU, in 2 tumors of PRO + 5-FU group and in 1 tumor of group with 5-FU and with PEN. Further studies are needed to elucidate if those modification of 5-FU action by the examined substances will be useful in the inhibition of the growth of Colon 38 cancer.
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PMID:Effects of short term treatment with pentagastrin, proglumide, tamoxifen given separately or together with 5-fluorouracil on the growth in the murine transplantable Colon 38 cancer. 1147 94

Human colorectal neuroendocrine cell carcinoma ( NECC ) is uncommon. Treatment of the disease has not yet been established, and NECC of the colon and rectum behave clinically more aggressively than their exocrine counterparts, so the prognosis is generally worse. One reason for the lack of established treatment is that there are no model systems of this disease. There have been a few reports on cell lines from neuroendocrine tumors, because these tumors are difficult to culture, and there are even fewer reports on colorectal carcinoma cell lines with neuroendocrine features. We therefore attempted to establish a permanent cell line in order to investigate the biological behavior and treatment of NECC. The cell line we succeeded in culturing is called N-TAK1. Gastrin promotes the growth of gastrointestinal epithelial cells and also stimulates the growth of gastrointestinal cancers. Hormone-receptor antagonists restrict the growth of hormone-dependent tumors. The growth of colon cancer was promoted by the application of gastrin, whereas it was restricted by proglumide, which is known to be a gastrin receptor antagonist. We demonstrated that gastrin has a stimulatory effect on the growth of N-TAK1 cells and that it could be detected by immunohistochemistry in the cells. We also showed that proglumide inhibited the growth effect of gastrin.
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PMID:Establishment and characterization of a human rectal neuroendocrine cell carcinoma in vitro. 1187 52

Gastrin is a gastrointestinal peptide that possesses potent trophic properties on both normal and neoplastic cells of gastrointestinal origin. Previous studies have indicated that chronic hypergastrinaemia increases the risk of colorectal cancer and cancer growth and that interruption of the effects of gastrin could be a potential target in the treatment of colorectal cancer. Here we demonstrate that gastrin leads to a dose-dependent increase in colon cancer cell proliferation and tumour growth in vitro and in vivo, and that this increment is progressively reversed by pretreatment with the cyclo-oxygenase-2 inhibitor NS-398. Gastrin was able to induce cyclo-oxygenase-2 protein expression, as well as the synthesis of prostaglandin E2, the major product of cyclo-oxygenase. Moreover, gastrin leads to approximately a two-fold induction of cyclo-oxygenase-2 promoter activity in transiently transfected cells. The results of these studies demonstrate that cyclo-oxygenase-2 appears to represent one of the downstream targets of gastrin and that selective cyclo-oxygenase-2 inhibition is capable of reversing the trophic properties of gastrin and presumably might prevent the growth of colorectal cancer induced by hypergastrinaemia.
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PMID:COX-2 selective inhibition reverses the trophic properties of gastrin in colorectal cancer. 1218 59

An increase in the risk of cancer is one of the consequences of obesity. The predominant cancers associated with obesity have a hormonal base and include breast, prostate, endometrium, colon and gallbladder cancers. As the basis for understanding the problem of obesity has advanced, a number of new ideas have emerged about the relationship of obesity to cancer. The conversion of androstenedione secreted by the adrenal gland into estrone by aromatase in adipose tissue stroma provides an important source of estrogen for the postmenopausal woman. This estrogen may play an important role in the development of endometrial and breast cancer. Of interest is that experimental animals lacking aromatase or the estrogen receptor alpha are obese. Leptin is one of the many products produced by fat cells and has given rise to the ideas that the fat cell is an endocrine cell and that adipose tissue is an endocrine organ. The increased release of cytokines from this tissue may play a role in the inflammatory state that is associated with obesity. The gut also plays an important role in signaling satiety in response to food intake. Colon cancer is an important human disease, and experimental mice lacking gastrin are obese and have an increased risk of developing colon cancer in response to carcinogenic drugs. Efforts to control obesity through preventive strategies and treatment can be expected to have a benefit in reducing the risk of cancer.
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PMID:The underlying basis for obesity: relationship to cancer. 1242 69

Gastrin has the ability to stimulate cell growth in some colorectal cancer cells and some of these cells also express gastrin/CCKB receptors, suggesting that gastrin and its autocrine loop are involved in their proliferation. We previously reported that oncogenic ras induced gastrin gene expression in colon cancer cells. The aim of this study was to investigate whether oncogenic ras also induces gastrin/CCKB receptor gene expression. A transiently transfected activated ras vector stimulated gastrin/CCKB receptor transcriptional activities in both Colo320HSR and LoVo cells, but these ras-increased activities were inhibited by a specific MEK inhibitor, PD98059. An RPA demonstrated that activated ras increased endogenous gastrin/CCKB receptor mRNA levels and PD98059 decreased them in LoVo cells. These findings suggest that oncogenic ras induces gastrin/CCKB receptor gene expression through some intracellular signaling pathways, including MEK, in colon cancer cell lines.
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PMID:Oncogenic ras induces gastrin/CCKB receptor gene expression in human colon cancer cell lines LoVo and Colo320HSR. 1276 77

We recently reported that downregulation of gastrin gene expression in colon cancer cells significantly suppresses relative levels of mitochondrial cytochrome c (cyt c) oxidase Vb (Cox Vb) RNA and protein. These unexpected findings suggested the possibility that gastrin gene products [mainly progastrin (PG)] may be directly or indirectly mediating the observed effects in colon cancer cells. Because colon cancer cells do not respond to exogenous PG, we examined the possibility of whether PG regulates Cox Vb expression in gastrin-responsive intestinal epithelial cells (IECs) in vitro. Levels of Cox Vb RNA and protein were significantly increased in a dose-dependent manner in response to PG. Mitochondrial synthesis of ATP was also increased by approximately three- to fivefold in response to optimal concentrations (0.1-1.0 nm) of PG. Possible antiapoptotic effects of PG were additionally examined, because activation of caspases 9 and 3 had been noted in colon cancer cells downregulated for gastrin gene expression. We measured a significant loss in the levels of cyt c in the cytosol of PG-treated vs. control IEC cells, which correlated with a significant loss in the activation of caspases 9 and 3, resulting in a significant loss in DNA fragmentation on PG treatment of the cells. Our results thus suggest the novel possibility that the precursor PG peptide exerts direct antiapoptotic effects on IECs, which may contribute to the observed growth effects of PG on these cells. Additionally, Cox Vb gene appears to be an important intracellular target of PG, resulting in an increase in ATP levels, which may also contribute to the observed increase in the growth of target cells in response to PG.
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PMID:Precursor peptide progastrin(1-80) reduces apoptosis of intestinal epithelial cells and upregulates cytochrome c oxidase Vb levels and synthesis of ATP. 1288 Dec 29


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